CN1320599A - Limited 9-cis-isotretinoins - Google Patents

Limited 9-cis-isotretinoins Download PDF

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Publication number
CN1320599A
CN1320599A CN00128089A CN00128089A CN1320599A CN 1320599 A CN1320599 A CN 1320599A CN 00128089 A CN00128089 A CN 00128089A CN 00128089 A CN00128089 A CN 00128089A CN 1320599 A CN1320599 A CN 1320599A
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China
Prior art keywords
compound
formula
methyl
tetrahydrochysene
naphthyl
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CN00128089A
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Chinese (zh)
Inventor
F·－L·秦
G·H·宾堡
J·W·艾斯坦
A·M·吉伯特
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Wyeth Holdings LLC
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American Cyanamid Co
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Priority claimed from US08/542,146 external-priority patent/US5968908A/en
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Publication of CN1320599A publication Critical patent/CN1320599A/en
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Abstract

The invention is novel analogs of 9-cis-retinoic acid which are useful for the treatment and prevention of coronary artery disease and to protect against premature atherosclerosis by increasing HDL levels. The invention includes processes for preparing the novel 9-cis-retinoic acid analogs.

Description

Limited 9-is suitable-retinoid
The application is that application number is 95113178.8 divides an application.
The application is the part subsequent application, i.e. the application number of 1994.12.19. submission is the subsequent application of US08/359141.
Comprise the molecule family control cytodifferentiation of natural and synthetic both Vogan-Neus (vitamin A) class and effective agent of hyperplasia (people J.Exp.Med. such as Wolbach, 42:753-777).High-density lipoprotein (HDL) (HDL), a kind of spheroidal particle that contains variable quantity lipid and apolipoproteins heterogamy population is a lipoprotein the abundantest in the blood plasma.Observe recently, low blood plasma HDL content is relevant with the increase of coronary artery disease (CAD) sickness rate.Epidemiological studies has confirmed this relation over nearly 30 years, and produces evidence to infer and increase HDL content and can be protected from CAD (Miller, N.E., Am Heart J, 113:589-597,1987).Can think, HDL transports system at lipid and plays an important role, the site that damage lipid that HDL expresses possibility and apolipoproteins transport storage, if they are not filled and enter hdl particle, because their potential decontamination and can damaging cells film (Eisenberg, S., J.Lipid Res.5:1017-1058,1984).
As everyone knows, high-density lipoprotein (HDL) comprises the metabolic processes of inequality in a large amount of blood vessels, comprises the reverse cholesterol transport process, and wherein cholesterol is transported to liver from extrahepatic tissue, so that convert bile and final movement to.Shown in observations, research makes great efforts to concentrate on the method that changes blood plasma HDL content, in order that the protection to CAD is provided.
As mentioned above, the spheroidal particle of HDL contains lipoprotein and Ah benefit's lipoprotein of various amounts.Apolipoproteins A-I (Apo A-I) is the major protein composition of blood plasma HDL, and is deutero-lipoprotein in the intestines, is called chylomicron.Though research points out that diet, hormone and other external environmental factor can be regulated the genetic expression of Apo A-I recently, the molecular basis of related mechanism is understood seldom.As everyone knows, the genes encoding of apolipoproteins A-I is mainly expressed in liver and intestines.Previous work shows, liver cell-special expression is decided by interaction collaborative between transcription factor, these factor utilizations are positioned at the special-purpose intensifying factor of liver strong on-222 to-110 positions of apolipoproteins A-I initiation site Nucleotide upstream and are bound to three isolating sites (people such as Widom, Mol.CellBiol., 11:677-678,1991).Find in the research that recently one of site is highly special vitamin A acid susceptibility factor RARE in this intensifying factor, can respond the retinoic acid receptor (RAR) RXR α that differentiates recently people such as (, Mol.Cell Biol., 11:3814-3820,1991.7) Rottman.These results suggest are expressed at apolipoproteins A-I by the vitamin A acid response approach that RXR α reconciles, final cholesterol, and retinoid transhipment and metabolic aspect work.People such as Ringer, Am.J.Chem.Nutr., 53:688-694,1991, the increase of observing patient HDL concentration is relevant with beta carotene, but does not find that apolipoproteins A or B content have any change.People such as Gollinich, at Saurat (ed.) Retinoids:New Find inResearch and therapy, Retinoid Symp., Geneva 1984, pp445-460 (Karger, Basel 1985) report, significantly change is not relevant with vitamin A acid salt (etretinoate) with the LDL aspect for cholesterol HDL among the patient, and reduces the HDL-cholesterol under with the retinoid condition.Lyons etc., Br.J.Dermotology, 107:591-595 (1982) observes, and the reduction of patient HDL-cholesterol is suitable with 13--and vitamin A acid is relevant.
The present invention relates to 9-suitable-vitamin A acid newly similar, they are disposed and treat coronary artery disease and be protected from early atherosclerosis by increasing HDL content.In addition, The compounds of this invention can be used for treating the cancer that the tumour cell variation is brought out.The present invention also comprise new 9-suitable-preparation technology of retinoid.The compounds of this invention is represented by the formula I:
Figure A0012808900201
The formula I is A wherein, and B and C are CH, CH 2, O or S, and no more than 1 of the heteroatoms that exists; D is (CH) m, M is the integer of 0-1; Perhaps D is (CH 2) n, n is the integer of 0-2; Dotted line ... expression exists or non-existent pair of key, if thereby only have two keys then think and be positioned at the a-b position, if having a plurality of pairs of keys then they are in conjugate position to form aromatic ring; R is a hydrogen, methyl, ethyl, the tertiary butyl or trifluoromethyl; Ar is as the lower section chemical formula:
Figure A0012808900202
R wherein 1, R 2, R 3And R 4Be hydrogen, (C 1-C 3) alkyl, (C 1-C 3) alkoxyl group or trifluoromethyl; As the lower section chemical formula:
Figure A0012808900211
R wherein 5Be hydrogen, (C 1-3) alkyl, methoxyl group or trifluoromethyl; And R 6Be hydrogen, methyl or ethyl; Or as the lower section chemical formula: R wherein 6Be hydrogen, methyl or ethyl; R 7Be hydrogen, methyl or ethyl; Y is that hydrogen and X are CH 2OH, CHO, COOH, CN, CH 2CONH 2Or as the lower section chemical formula: Or
Figure A0012808900214
R wherein 8Be straight or branched (C 1-8) alkyl, or Here R 9Be hydrogen, straight or branched (C 1-10) alkyl, glycosyl, the 2-methoxyethyl, 2-diformazan aminoethyl, (1,2, or 3)-pyridyl, or (1,2, or 3)-picolyl; Perhaps X and Y connect together and form the thiazolidinedione ring of following formula:
Figure A0012808900222
And their pharmacologically acceptable salts and ester.
The preferred embodiment of formula I compound is:
Figure A0012808900223
The formula I is A wherein, and B and C are CH, CH 2, O or S, and no more than 1 of the heteroatoms that exists; D is (CH) m, m is the integer of 0-1; Perhaps D is (CH 2) n, n is the integer of 0-2; Dotted line ... expression exists or non-existent pair of key, if thereby only have two keys then be positioned at the a-b position, if having a plurality of pairs of keys then they are in conjugate position to form aromatic ring; R is a hydrogen, methyl, ethyl, the tertiary butyl or trifluoromethyl; Ar is as the lower section chemical formula: R wherein 1, R 2, R 3And R 4Be hydrogen, (C 1-3) alkyl, (C 1-3) alkoxyl group or trifluoromethyl; Y is that hydrogen and X are CH 2OH, CHO, COOH, CN, CH 2CONH 2Or as the lower section chemical formula: , or R wherein 8Be straight or branched (C 1-8) alkyl, or-C-HR 9, R here 9Be hydrogen, straight or branched (C 1-10) alkyl, glycosyl, the 2-methoxyethyl, 2-diformazan aminoethyl, (1,2, or 3)-pyridyl, or (1,2, or 3)-picolyl; Perhaps X and Y connect together and form the thiazolidinedione ring of following formula: And their pharmacologically acceptable salts and ester.
Other preferred embodiment of formula I is: The formula I is A wherein, and B and C are CH, CH 2, O or S, and no more than 1 of the heteroatoms that exists; Y is a hydrogen; D is (CH) m, m is the integer of 0-1; Perhaps D is (CH 2) n, n is the integer of 0-2; Dotted line ... expression exists or non-existent pair of key, if thereby only have two keys then be positioned at the a-b position, if having a plurality of pairs of keys then they are in conjugate position to form aromatic ring; R is a hydrogen, methyl, ethyl, the tertiary butyl or trifluoromethyl; Ar is as the lower section chemical formula: R wherein 5Be hydrogen, (C 1-3) alkyl, methoxyl group or trifluoromethyl; R 6Be hydrogen, methyl or ethyl; Y is that hydrogen and X are CH 2OH, CHO, COOH, CN, CH 2CONH 2Or as the lower section chemical formula:
Figure A0012808900252
, or R wherein 8Be straight or branched (C 1-8) alkyl, or
Figure A0012808900254
Here R 9Be hydrogen, straight or branched (C 1-10) alkyl, glycosyl, the 2-methoxyethyl, 2-diformazan aminoethyl, (1,2, or 3)-pyridyl, or (1,2, or 3)-picolyl; Perhaps X and Y connect together and form the thiazolidinedione ring of following formula:
Figure A0012808900261
And their pharmacologically acceptable salts and ester.
Other preferred embodiment of formula I is:
Figure A0012808900262
The formula I is A wherein, and B and C are CH, CH 2, O or S, and no more than 1 of the heteroatoms that exists; Y is a hydrogen; D is (CH) m, m is the integer of 0-1; Perhaps D is (CH 2) n, n is the integer of 0-2; Dotted line ... expression exists or non-existent pair of key, if thereby only have two keys then be positioned at the a-b position, they are in conjugate position to form aromatic ring if there are a plurality of pairs of keys; R is a hydrogen, methyl, ethyl, the tertiary butyl or trifluoromethyl; Ar is as the lower section chemical formula:
Figure A0012808900271
R wherein 6Be hydrogen, methyl or ethyl; R 7Be hydrogen, methyl or ethyl; Y is a hydrogen, and X is CH 2OH, CHO, COOH, CN, CH 2CONH 2Or as the lower section chemical formula:
Figure A0012808900272
, or
Figure A0012808900273
R wherein 8Be straight or branched (C 1-8) alkyl, or Here R 9Be hydrogen, straight or branched (C 1-10) alkyl, glycosyl, the 2-methoxyethyl, 2-diformazan aminoethyl, (1,2, or 3)-pyridyl, or (1,2, or 3)-picolyl; Perhaps X and Y connect together and form the thiazolidinedione ring of following formula:
Figure A0012808900281
And their pharmacologically acceptable salts and ester.
According to reaction skeleton diagram 1,
Reaction scheme Fig. 1
Figure A0012808900291
The compound of formula ArBr or ArI, wherein Ar such as top qualification, with the lithium alkylide reaction such as tert-butyl lithium, condition is to carry out 1-5 hour in-78 ℃ to 30 ℃ temperature in such as the inert solvent of tetrahydrofuran (THF), uses ZnCl subsequently 2, obtain the compound of formula ArZnCl, this compound itself and the reaction of formula II compound,
Figure A0012808900301
The formula II is A wherein, B, C, D and dotted line ... qualification the same, exist such as Pd[P (C 6H 5) 3] 4 palladium ° catalyzer; In such as the inert solvent of tetrahydrofuran (THF), reacted 1-5 hour in 10-60 ℃; Obtain formula III compound: The formula III
Formula III compound, Ar wherein, A, B, C, D and dotted line ... qualification the same, by such as the reduction of the hydride reducer of lithium aluminium hydride, such as the inert solvent of ether or tetrahydrofuran (THF) in 0-60 ℃ of reaction 0.5-6.0 hour; Obtain formula IV compound: The formula IV
Formula IV compound with such as the phosphine reaction of triphenylphosphine hydrogen bromide, Ar wherein, A, B, C, D and dotted line ... qualification the same, obtain formula V compound:
Figure A0012808900311
The formula V
Formula V compound with such as potassium hydroxide, the alkali reaction of sodium methylate or sodium ethylate, such as methyl alcohol, in the solvent of ethanol or tetrahydrofuran (THF) in 0 ℃ of reaction 0.5-3.0 hour, add subsequently a kind of as shown in the formula aldehyde: Wherein the R qualification is the same, and X is COOR 8And R 8Limit the samely, Y is a hydrogen, obtains formula I compound.
According to skeleton diagram 2, formula I compound with such as the reaction of the hydride reducer of lithium aluminium hydride,
Figure A0012808900313
Ar wherein, A, B, C, D, R, Y and dotted line ... qualification the same, X is COOH or COOR 8, and R 8Limit the same, in such as the inert solvent of tetrahydrofuran (THF) in 0-60 ℃ the reaction 0.5-3.0 hour, obtaining X is CH 2The formula I compound of OH.Then with the gained compound with such as the oxidant reaction of Manganse Dioxide, obtain X and be-CHO and Y is the formula I compound of hydrogen.
Reaction scheme Fig. 2
As selection, shown in Figure 3 as square frame, formula I compound with under hydrolysising condition, react in water such as the alkali of sodium hydroxide or potassium hydroxide, Y is a hydrogen in the formula I, X is COOR 8And R 8Limit the same, in 30-100 ℃ the reaction 0.5-8 hour, the mineral acid acidifying with all example hydrochloric acids subsequently obtains the formula I compound that X is COOH.
Reaction scheme Fig. 3
Formula I compound, Ar wherein, A, B, C, D and dotted line ... and the qualification of R and Y is the same, and X is COOH, and with itself and the reaction of a kind of activator, activator is selected from the phosphinylidyne diimidazole, thionyl chloride, the chloroformic acid tert-butyl ester, PCl 3, POCl 3, PCl 5, in such as tetrahydrofuran solvent,, when activator is the phosphinylidyne diimidazole, obtain the intermediate product of formula VI in 0-25 ℃ of reaction 0.5-1 hour:
Figure A0012808900341
To adding type R wherein 9NH 2A kind of amine, R 9Limit the samely, obtain the acid amides of formula VII: The formula VII is Ar wherein, A, B, C, D, Y, dotted line ... the same with the qualification of R9.
According to skeleton diagram 4, formula IV compound is used such as activatory Manganse Dioxide reagent oxidation,
Figure A0012808900351
Ar in the formula IV formula, A, B, C, D and dotted line ... limit the same, in such as the solvent of methylene dichloride in 0-40 ℃ the reaction 0.5-6.0 hour, obtain formula VIII compound:
Figure A0012808900352
The formula VIII is with the interior reactant salt of it and following formula: Wherein R is a hydrogen, methyl, the tertiary butyl or trifluoromethyl; Under the alkali situation of existence such as sodium hydride, in having, react the formula I compound that obtains, Ar wherein, A, B, C, D and dotted line such as tetrahydrofuran solvent ... and the qualification of R is the same, and X is COOC 2H 5
Reaction scheme Fig. 4
Reaction scheme Fig. 5
Figure A0012808900371
The formula VIII
According to scheme 5, with the ketal of (wherein A, B, C and D such as above-mentioned definition) in the above-mentioned chemical formula and a kind of alkali such as n-Butyl Lithium at a kind of solvent, as reacting under 0 ℃ in-78 ℃ in the tetrahydrofuran (THF), then add boric acid ester such as triisopropyl boric acid ester, be hydrolyzed into boric acid again.The aryl halide of boric acid and a kind of chemical formula ArZ (wherein Z is a bromine or iodine) is at room temperature reacted, have a kind of palladium (O) to make catalyzer such as tetrakis triphenylphosphine palladium (O), then make the aldehyde of chemical formula VIII by acid hydrolysis.
Reaction scheme Fig. 6
Figure A0012808900381
The formula III
According to scheme 6, the aromatic bromide (wherein Ar as above defines) of a kind of chemical formula ArBr is reacted down in-78 ℃ to 0 ℃ in solvent such as tetrahydrofuran (THF) with a kind of alkali such as n-Butyl Lithium, then add acid esterification thing such as triisopropyl boric acid ester, being hydrolyzed into chemical formula again is ArB (OH) 2Boric acid, with the compound reaction of itself and a kind of following chemical formula, Condition is: wherein A, B, C and D as above define, and Z is a bromine or iodine, at a kind of solvent such as glycol dimethyl ether, a kind of palladium (O) catalyzer are arranged, and exist down as tetrakis triphenylphosphine palladium (O) and yellow soda ash, then make a kind of compound of formula III defined above.
Biology
Apolipoproteins (Apo A-I) is the major protein composition of blood plasma HDL, many epidemiology, sends and pass to learn and biochemical research provides strong evidence for high blood plasma HDL concentration can prevent this viewpoint of early atherosclerosis.
The physiology hormone of retinoic acid receptor (RAR) (RAR) and vitamin A acid (X) acceptor (RXR) according to push away then be respectively be all-trans-vitamin A acid (RA) and 9-be suitable-vitamin A acid (the suitable RA of 9-).Yet, 9-along RA can in conjunction with and transcriptional activation RAR simultaneously.For make RAR be attached to that vitamin A acid replys that composition (RARES) is gone up and effectively modificator gene transcribe, they must form allodimer with RXRS.Yet if exist 9-along under the RA condition, RXR can form equal dipolymer, its can in conjunction with and activate special genes.
New compound of the present invention can improve serum content and the HDL of apolipoproteins A-I in the mouse body, and they show it is to dispose the therapeutical agent that low HDL causes the disease situation, the mankind's that cause as low HDL atherosclerosis.
The member of the especially big family of nuclear receptor (comprising RXR α) but activated transcription, it is by being attached to (Science 240,889 (1988) for Evans, R.) that finish in the site of the same clan that is positioned on the target gene initiation site near zone DNA.The biological results electrophoretic mobility shifts evaluation and test
This synthetic retinoic acid-like shifts Evaluation Method (EMSA) with electrophoretic mobility and tests, and wherein the associated ligands that is attached on the site A of Apo A-I gene promoter of RXR α is supervised then (MCB 11,3814 (1991) for Rottman, J.N.).The RXR α that will obtain from the E.COli that includes a kind of RXR α-expression plasmid is purified to homogeneous state by affinity chromatography.Concerning EMSA, protein purification is not or have under the retinoid situation with containing hatching as radio-label mark oligonucleotide probes of site A sequence.RXR α-DNA mixture never fetters in the probe and is dissolved out (D.M., Nucleic AcidResearch 9,6505 (1981) for Fried, M. and Crothers) in electrophoresis mode on the unmodified polyacrylamide silica gel.
9-Cis-RA is the native ligand of RSR α, and it may promote RXR α to be attached to (Zhang, X.K. wait the people, and Nature 358,587 (1992)) on the probe by promoting equal dipolymer to form.Excessive transfer by oligonucleotide competition and antibody is assessed, and this 9-Cis-RA inductive mixture is specific (Rottman, J.N., McB11,3814 (1991)).Contrast effectiveness to testing compound determines that by range estimation autoradiogram intensity example is among table 1 as a result.
Table 1
The compound title Effectiveness with respect to 9-Cis-RA
E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid ????5 +
E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid ????5 +
E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-1-cyclopentenes-yl]-2, the 4-pentadienoic acid ????4 +
3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-phenyl]-2, the 4-pentadienoic acid ????4 +
E, E-3-methyl-5-[-2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid ????3 +
E, E-3-methyl-5-[2-(1,1,3,3-tetramethyl--1,3-dihydro (5-isobenzofuran-base)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid ????2 +
Table 1 (continuing)
The compound title Effectiveness with respect to 9-Cis-RA
3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) phenyl]-2, the 4-pentadienoic acid ????1 +
3-methyl-TTNEB *(prior art compound) ????1 +
*3-methyl-TTENB (Boehm, M. wait the people, world patent publication number: WO 93/,211 46, and WIPO, October 28,1993, structure such as following).The mensuration of serum hdl and Apo A-I in the body
Use male Wister mouse (190-210g) to measure the serum content of HDL under study for action.Compound is suspended in the sweet oil of sterilization with the concentration of 20mg/ml.Before beginning one's study, make the mouse bloodletting with back socket of the eye puncture method, then with the 100mg/kg/ dosage peritoneal injection administration retinoid of every day.Total volume injected is that the 1ml sweet oil is equipped with the 1ml medicine and is expelled in the vector body.To mouse injection 4 days, inject back 24 hours the last time with the bloodletting of heart puncture method.Blood collecting is in EDTA, and blood plasma is used to analyze HDL cholesterol, total cholesterol and Apo A-I.
To E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-1-cyclopentenes-1-yl]-2, (Boehm, M. wait the people for 4-pentadienoic acid, 3-methyl-TTNEB, world patent publication number: Wo 93/21146, WIpo, on October 28th, 1993, structure is following) and all the measuring result example of anti--retinoid in table 2.
Table 2
The contrast percentage amounts changes
The compound title The HDL cholesterol Apo?A-I
E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid +32％ +70％
3-methyl-TTNEB (compound of the prior art) +41％ +4％
Whole anti--vitamin A acids (compound of prior art) -9％ -71％
Those bring out differentiation reagent oneself think the surrogate of the cytotoxicity method of disposal in cancer therapy.Instead-vitamin A acid successfully is used in to alleviate suffers from promyelocyte leukaemic (R.P.Warrell, Deng the people., New England Journal of Medicine, Vol.324,1385-1393,1991], it can bring out HL-60 promyelocyte leukemia cell differentiation capability to compound test of the present invention.CD11b expresses: 2.5 * 10 5The HL60 cell was cultivated 3 days with the medicine series diluent.Cell PBA (Dulbecco ' s PBS (W/out Ca ++And Mg ++), 0.1% N serum albumin and the trinitride of 0.1% sodium) washing, (Pharmigen Cat#30451A) cultivated 1 hour down in 4 ℃ to be used in the Anti-Human's class CD11b monoclonal antibodies of 1.6 μ g/ml mouse among the PBA again.Cell washs with PBA, resists-mouse IgG-FITC (Becton DicKinson, diluent cultivation in 1: 50 Cat#349031) 1 hour with the goat that is dissolved among the PBA down in 4 ℃ again.Cell washs secondary with PBA, and resuspending is analyzed in PBS and deriving from the FACSort instrument of Becton Dickinson.The result of table 3 shows that the compound of example 2 and example 4 brings out the identical of HL-60 cell differentiation and 9-Cis-vitamin A acid.
Table 3
Embodiment The compound title %CD 11b positive cell 10 μ g/ml compounds
???2 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid ????50
???4 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-(cyclopentenes-1-yl] 2, the 4-pentadienoic acid ????50
???6 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid ????3
???8 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid ????5
The 9-Cis vitamin A acid ????58
E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid
Figure A0012808900462
3-methyl-TTNEB
(compound of prior art)
Figure A0012808900463
Be all-trans-vitamin A acid
(compound of prior art)
Compound of formula I can be made medicinal salts and ester class.Salt can be an alkali metal salt such as sodium, potassium and lithium salts; Alkaline earth salt such as calcium, ammonia salt; Organic salt such as triethyl ammonium salt, morpholine, N-methylmorpholine etc.Their available methods known to those skilled in the art (Richard C.Larock, Comprehensive Organic Transformations, VCH Publishers, 411-415,1989) prepare.Know that by those skilled in the art's known technology selecting suitable salt is to confirm according to its physics and chemical stability, flowability, water absorbability and solubility.
Formula I compound of the present invention can and be used oral administration with a kind of pharmaceutical carrier, can be used to treatment and prevention coronary artery disease, and is used to prevent early atherosclerosis.
When compound of the present invention was used for above-mentioned purposes, they can be used in combination with one or more pharmaceutical carriers, for example solvent, thinner etc.; Can adopt the form oral administration of following formulation, but these formulations such as tablet, wafer dispersion powder, pill or contain according to appointment the suspension of 0.05 to 5% suspension agent; Contain the syrup of 10～50% sugar according to appointment; Contain 20～50% alcoholic acid elixirs etc. according to appointment; But they are the intestines external administration also, as with aseptic parenteral solution or use by containing at the suspension that waits the suspension agent that oozes about 0.05～5% in the medium to constitute.These medicinal formulas can contain 25～90% active ingredient according to appointment, and these active ingredients and carrier (weight usually) content range is 5 to 60%.
The effective level of these compounds is 2.0 to 100.0mg/ body weight kg; The administration frequency is every day 1 to 5 time; Route of administration can be the approach of any routine, comprises (but being not limited to this): (comprising subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques), administration epidermis or rectum that oral, intestines are outer; Contain conventional non-toxicity pharmaceutical carrier, adjutant and vehicle in its form formula.Yet what be readily appreciated that is concerning a certain specific patient, special dosage level is different with the consumption frequency, this depends on multiple factor, comprises that the mode of the metabolic stability of activity, compound of used specific compound and action time, age, body weight, healthy state, sex, dietary structure, administration and time, discharge rate, medicine are in conjunction with situation, patient's the special state of an illness and the therapeutic process of usefulness.
These active compounds can be taken orally, can also intravenous, intramuscular or subcutaneous route administration.Solid-state carrier comprises starch, lactose, Lin Suanergai, Microcrystalline Cellulose, sucrose, kaolin; Liquid carrier comprises sterilized water, polyoxyethylene glycol, nonionogenic tenside and edible oil such as soybean, peanut and sesame oil, and they are suitable for the character of active ingredient and are needed form of medication.The conventional adjuvant that is used for the medicinal compositions preparation all is useful, comprises as perfume agent, tinting material, preservatives and antioxidant such as vitamin E, anti-bad thrombus, BHT and BHA.
From the viewpoint that is easy to prepare and be convenient to take, preferred medicinal compositions is a solids composition, particularly the wafer of filling of tablet and hard or liquid filling.The compound oral administration is preferred.
These active compounds also can the outer or intraperitoneal administration by intestines.Solution or suspension as these active compounds of free alkali and pharmaceutical salts can and prepare in the mixture in oil at glycerine, liquid, poly-ethanol.Under general storage and working conditions, these formulations can contain preservatives to suppress microbial growth.
The medicinal forms that is suitable for injecting use comprises aseptic aqueous solution or dispersion agent and prepares the sterilized powder of aseptic injectable solution or dispersion liquid temporarily.In all cases, medicament must be aseptic, and must be to flow to the to a certain degree feasible injection that is easy to.It should be stable under manufacturing and storage case, must make the contamination of avoiding microorganism such as bacterium and fungi during preservation.Carrier can be a kind of solvent or dispersion medium, includes as water, ethanol, polyvalent alcohol (as glycerine, polyoxyethylene glycol and liquid macrogol), its suitable mixture and vegetables oil.
These compounds also can be encapsulated in the liposome, so that allow the intravenous administration of medicine.The liposome that is suitable among the present invention is a lipid capsule, it comprises multi-disc layer lipid capsule, little Sonicated multi-disc layer capsule, reverse-phase evaporation capsule, large-scale multi-disc layer capsule etc., wherein, lipid capsule is to be formed by one or more phosphatide, these phosphatide such as Yelkin TTS, phosphatidyl glycerol ester, sphingomyelin, phosphatidyl lactic acid etc.
The following examples have described the synthetic of typical compound of the present invention in detail.These steps are illustrative, the present invention should not regarded as the qualification that is subjected to its chemical reaction of explaining and condition.Also not making great efforts to make the productive rate in these reactions to reach optimizing, is conspicuous for those of ordinary skill in the art by changing reaction times, temperature, solvent and/or reagent raising productive rate.
Embodiment 1
Z, E and E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid ethyl ester
To the solution of 2.0 gram 2-bromo-(5,6,7,8-tetrahydrochysene-5,5,8, the 8-tetramethyl-) naphthalenes that stir,, then add the zinc chloride in the 0.5m tetrahydrofuran (THF) of 15ml in-78 ℃ of tert-butyl lithium that add the 1.7M that is dissolved in pentane of 9ml down at the anhydrous tetrahydro furan of 20ml.With this mixture heating up to room temperature, add four [triphenylphosphine] palladium (0) of 0.39 gram and the 2-trifluoromethane-sulfonyloxy tetrahydrobenzene-solution of 1-yl carboxylic acid ethyl ester in the tetrahydrofuran (THF) of 5ml of 1.0 grams again, obtained solution stirred 2 hours under the reflux temperature of solvent.Reactant is cooled to room temperature, adds the ether of 50ml, separates the stratiform thing.Organic layer is water, aqueous carbonic acid hydrogen sodium, saturated sodium-chloride washing respectively, does quick-fried with sodium sulfate.Evaporating solns is by chromatography (silica gel: hexane/ether 4: 1) obtain 1.5 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-the naphthyl)-1-tetrahydrobenzene-1-carboxylic acid, ethyl esters that restrain, be colorless solid.
The solution that will be dissolved in the above-mentioned separate solid of 1.48g in the 15ml ether is added drop-wise to the 1.0N lithium aluminum hydride of 10ml in anhydrous tetrahydro furan under 0 ℃, then at room temperature stirred 15 minutes.Water droplet is added in the refrigerative reaction mixture.The reactant ether extraction.Compile organic layer and use dried over sodium sulfate, evaporation obtains a kind of buttery alcohol.This oil is dissolved in the methyl alcohol of 60ml, and to the triphenylphosphine hydrobromide that wherein adds 1.5 grams, at room temperature stirred reaction mixture is 17 hours.Vacuum is removed solvent, and resistates makes corresponding phosphonium bromide with the ether washing, then it is dissolved in the dry dichloromethane of 25ml, is cooled to 0 ℃ in the argon gas, adds 3-methyl-4-oxo butenoic acid ethyl of sodium ethylate and 0.7ml.Mixture stirred 1 hour down at 0 ℃, and water is stopped reaction suddenly.The dichloromethane extract dried over sodium sulfate is evaporated to a kind of reddish oil, with chromatographic purification (silica gel: hexane/ether 9: 1) obtain 1.1 E that restrain, E and Z, 15: 2 mixtures of E ester.
Embodiment 2
E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid
Mixing (15: the 2) ester products that will be obtained by example 1 stirred 3 hours under reflux temperature with the 10ml methanol mixed that 5ml contains the 2N aqueous potassium hydroxide.Reaction mixture is cooled to room temperature, is poured in ice and the dichloromethane mixture, uses the 3N hcl acidifying to pH3.Compile organic layer,, make a kind of light yellow solid with dried over sodium sulfate, evaporation.This solid recrystallization from dehydrated alcohol obtains 0.5 gram expecting compound, is clear crystal.Mp198-199 ℃; 1H NMR (CDCl 3): δ 1.24 (s, 6H), 1.26 (s, 6H), 1.69 (s, 4H), 1.76-1.82 (m, 4H), 2.10 (s, 3H), 2.32-2.39 (m, 2H), 2.46-2.50 (m, 2H), 5.77 (s, 1H), 6.25 (d, J=16.0Hz, 1H), 6.86 (d, J=16.0Hz, 1H), 6.95 (d, J=7.0Hz, 1H), 7.06 (s, 1H), 7.28 (d, J=7.0Hz, 1H) 13C NMR (CDCl 3) downfield of ppm TMS: 13.90,22.52,22.78,22.91,25.66,31.80,31.90,33.05,34.10,34.22,35.06,35.14,116.93,125.46,126.16,127.56,128.58,129.96,136.46,139.26,143.66,144.15,144.49,156.33,172.39.IR (KBr): 3054,2959,2928,2861,1593,1679,1595,1491,1457,1363,1349,1262,1188,963,878cm -1.MS (CI): m/z 379.UV (in CH 3OH): 317.nM.
Embodiment 3
Z, E and E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,8,8-tetramethyl--2-naphthyl)-1-cyclopentenes-1-yl]-2,4-pentadienoic acid ethyl ester
According to the step of example 1, use 2-trifluoromethane sulphonyl oxygen cyclopentenes-1-yl carboxylic acid ethyl ester, with E, E-and Z, 13: 3 mixtures of E-isomer obtain title compound, separate and obtain each isomer with chromatographic purification.
Embodiment 4
E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid
This title compound is according to the step of embodiment 2, uses mixing (13: the 3) ester products that is made by example 3 of 1.19 grams, obtains the desired product of 0.5 gram thus.
mp=197-198℃.
1H?NMR(CDCl 3):δ1.30(s,12H),1.70(s,4H),1.98-2.03(m,
2H),2.29(s,3H),2.72(t,J=7.0Hz,2H),2.90(t,J=7.0Hz,
2H),5.?83(s,1H),6.29(d,J=16.0Hz,1H),
7.10(d,J=7.0Hz,1H),7.14(d,J=16.0Hz,1H),7.28(s,H),
7.31(d,J=7.0Hz,1H).
13C NMR (CDCl 3) downfield of ppm TMS: 13.90,21.81,
22.81,31.77,31.86,33.74,34.20,35.05,38.70,117.45,
125.01,126.54,126.88,131.36,132.69,134.51,135.23,
144.29,144.62,146.50,155.83,172.03.
IR(KBr):3447,3314,3052,2958,2926,2865,1679,1592,
1457,1436,1414,1386,1363,1281,1256,1186,967,
905,826cm -1.
MS(CI):m/z?364(M +)
UV(in?CH 3OH):323nM.
Embodiment 5
Z, E-and E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid ethyl ester
(78 ℃) of court-stirring contain 4.2 gram 2-bromo-3,5,5,8,8-pentamethyl--5,6,7, the tert-butyl lithium (1.7N pentane) of adding 18ml in the tetrahydrofuran solution of the 40ml of 8-naphthane.Reaction mixture stirred 1 hour down at-78 ℃, was heated to room temperature, restir 1 hour.The tetrahydrofuran solution that 30ml contains the 0.5M zinc chloride adds wherein and lasting the stirring 1 hour.The tetrahydrofuran solution of the tetrakis triphenylphosphine palladium (O) that contains 2-trifluoromethane sulfonyloxy tetrahydrobenzene-1-yl carboxylic acid ester and 0.8 gram of 3 grams adds wherein, and reaction mixture heated 3 hours under reflux temperature.According to the treating processes of embodiment 1, make 2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-the naphthyl)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester of 2.75 grams.Above-mentioned isolating ester is reduced into corresponding alcohol with the lithium aluminium hydride that is dissolved in the ether, then its method by example 1 is changed into the bromination triphenylphosphine.Bromizate thing and the dichloromethane solution reaction that contains 3-methyl-4-oxo butenoic acid ethyl and sodium ethylate by example 1 method, then obtain title compound, it is the E of 8: 1 ratios, E and Z, the mixture of E ester.Ester is separated into independent isomer by chromatography.
Embodiment 6
E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid
This title compound adopts mixed ester (8: the 1) product of 1.08 grams that obtained by example 5 according to the program preparation of example 2, then obtains the expectation product of 0.65g.
mp?208-209℃.
1H?NMR(CDCl 3):δ1.21(s,3H),1.25(s,3H),1.27(s,3H),
1.28(S,3H),1.67(s,4H),1.69-1.78(m,4H),1.98(s,3H),
2.08(s,3H),2.30-2.33(m,4H),5.73(s,1H),
6.18(d,J=16.0Hz,1H),6.44(d,J=16.0Hz,1H),6.87(s,1H),
7.08(s,1H).
13C NMR (CDCl 3) downfield of ppm TMS: 13.58,19.06,
22.64,22.78,24.94,31.72,31.77,31.93,32.13,32.98,
33.91,35.21,116.82,126.62,127.70,128.15,130,30,
131.94,136.00,139.10,141.98,143.39,145.03,156.21,
171.71.
IR(KBr):3048,3016,2958,2929,2595,1677,1598,
1496,1390,1362,1349,1261,1189,963,879?cm -1.
MS(CI):m/z?393(M ++H)
UV(in?CH 3OH):306?nM
Embodiment 7
Z, E and E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentenes-1-yl]-2,4-pentadienoic acid ethyl ester
Step by example 1 prepares title compound, uses 2-trifluoromethane sulphonyl oxygen cyclopentenes-1-yl carboxylic acid ethyl ester, then obtains 17: 5 isomer mixture, by chromatography it is separated into isomer separately.
Embodiment 8
E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid
Title compound uses the isomer mix products that is obtained from example 7 by the preparation of example 2 steps, then makes institute's phase product.
mp?207-208℃.
1H?NMR(CDCl 3):δ1.25(s,6H),1.29(s,6H),1.67(s,4H),
2.02(q,J=7.0Hz,2H),2.16(s,3H),2.18(s,3H),2.62-
2.68(m,2H),2.71-2.80(m,2HO,5.80(s,1H),
6.24(d,J=16.0Hz,1H),6.68(d,J=16.0Hz,1H),6.95(s,1H),
7.11(s,1H).
13C NMR (CDCl 3) downfield of ppmTMS: 13.45,19.67,
22.30,31.55,31.64,32.39,33.62,33.70,34.91,38.93,
118.61,127.38,127.88,129.82,132.09,132.37,134.22,
136.52,141.59,143.55,147.21,152.86,169.03.
IR(KBr):3014,2957,2864,2585,1683,1595,1495,1455,
1416,1362,1347,1257,1186,963,909,877cm -1.
MS(CI):m/z?379(M ++H).
UV(in?CH 3OH):316nM.
Embodiment 9
E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid acid amides
Being obtained from example 2 and being dissolved in product in the anhydrous tetrahydro furan to monovalent in 0 ℃ of carbonyl dimidazoles that adds down monovalent.Through after 0 ℃ of stirring in following 30 minutes, dry ammonia blasts in the reaction mixture, and continues to stir 1 hour under room temperature.Solvent is in vacuum concentration, and the product of expection is with recrystallization in the ethanol.
Embodiment 10
N-(2-methoxyethyl)-E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid acid amides
Use 2-methoxy ethamine to prepare title compound according to the step of example 9.
Basically according to the example 9 of above-detailed and 10 method, prepare the compound in the table 4.
Table 4
The embodiment numbering Starting acid Reagent Product
????11 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid The 3-aminomethyl-pyridine N-(3-pyridylmethyl)-E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid acid amides
????12 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid 2-dimethylamino ethamine N-(2-dimethylaminoethyl)-E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-tetrahydrobenzene-1-yl]-2, the 4-Pentadienamide
????13 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid The 3-aminopyridine N-(3-pyridyl)-E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid acid amides
????14 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid NH 3 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-cyclopentenes-1-yl]-2,4-pentadienoic acid acid amides
????15 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid CH 3OCH 2CH 2NH 2 N-(2-methoxyethyl)-E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-cyclopentenes-1-yl]-2,4-pentadienoic acid acid amides
Table 4 (continuing)
The embodiment numbering: Starting acid Reagent Product
????16 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid The D-glycosamine E, E-N-(2-deoxy-glucose base)-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-cyclopentenes-1-yl]-2,4-pentadienoic acid acid amides
????17 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid L-Ala, the tert-butyl ester N-[E; E-3-methyl-5-[2-(5; 6; 7,8-tetrahydrochysene-5,5; 8; 8-tetramethyl--2-naphthyl)-and 1-cyclopentenes-1-yl]-2,4-pentadiene acyl group] L-Ala, the tert-butyl ester
????18 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid NH 3 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-cyclopentenes-1-yl]-2,4-pentadienoic acid acid amides
????19 E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid NH 3 E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid acid amides
????20 E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid Glycine, the tert-butyl ester N-[E; E-3-methyl-5-[2-(3; 5,5,8; 8-pentamethyl--5; 6,7,8-tetrahydrochysene-2-naphthyl)-1-tetrahydrobenzene-1-yl]-2; 4-pentadiene acyl group] glycine, the tert-butyl ester
Table 4 (continuing)
The embodiment numbering: Starting acid Reagent Product
??21 E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid CH 3OCH 2CH 2NH 2 N-(2-methoxyethyl)-E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid acid amides
??22 E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid NH 3 E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentenes-1-yl]-2,4-pentadienoic acid acid amides
??23 E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid CH 3OCH 2CH 2NH 2 N-(2-methoxyethyl)-E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentenes-1-yl]-2,4-pentadienoic acid acid amides
??24 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-and 1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid CH 3OCH 2CH 2NH 3 N-(E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid acid amides
Embodiment 25
5-bromo-1,1,3,3 ,-tetramethyl--1,3-dihydroisobenzofuran
5.0g 4-bromobenzene dioctyl phthalate to be dissolved in the solution of anhydrous methanol of 200ml saturated with anhydrous hydrogen chloride gas, and at room temperature stirred 20 hours.Reaction mixture vacuum-evaporation, remaining on spends the night under the high vacuum then makes dimethyl-4-bromobenzene dicarboxylic acid esters of 5.13g, is a kind of slightly yellow oil. 1H?NMR(CDCl 3):δ3.90(S,3H)；3.92(S,3H)；7.62(d,J=8.3Hz,1H)；7.67(dd,J=8.3Hz,1.8Hz,1H)；7.84(d,J=1.8Hz,1H)。
The mixture that the above-mentioned product of 27.3g is dissolved in the tetrahydrofuran (THF) of 100ml places ice bath to cool off.Dripped the tetrahydrofuran solution that contains the 3.0M methylmagnesium-chloride of 200ml through 30 minutes towards this cooling mixture.After adition process finished, reactant heat 24 hours under reflux temperature, was poured in the saturated ammonium chloride of 400ml quick stoppage and reacted, and used ether extraction.Whole organic layers with saturated sodium-chloride washing, with sodium sulfate do quick-fried, filter, evaporation, then make the buttery crude product.Crude product obtains 2,2 of 9.55g '-(4-bromo-1,2-phenylene) two (2-propyl alcohol) after with the hexane crystallization. 1H?NMR(CDCl 3):δ1.69(S,6H)；1.70(S,6H),4.97(brs,2H)；7.18(d,J=8.6Hz,1H)；7.28(dd,J=8.7Hz,2.22Hz,1H)；7.44(d,J=2.Hz,1H)。
The above-mentioned diol product that in 60% sulfuric acid of 26ml, adds 2.92g.Mixture heated 1 hour down for 50 ℃.In reaction mixture impouring water, use hexane extraction.Whole hexane layers again with saturated sodium-chlor washing, is used dried over sodium sulfate with saturated sodium bicarbonate, by short plate filtration, the evaporation of hydrated magnesium silicate, then makes the expection title compounds of 2.47 grams of white solid. 1H?NMR(CDCl 3):δ1.49(S,6H)；1.50(S,6H)；6.96(d,J=8.0Hz,1H)7.22(d,J=1.6Hz,1H)；7.39(dd,1.7Hz,1H)。
Embodiment 26
E, E and Z, E-3-methyl-5-[2-(1,1,3,3-tetramethyl--1,3-dihydro-5-isobenzofuran-base)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid ethyl ester
Adopting the step of example 1, make the product of use-case 25 make this title compound, is E, E and Z, the mixture of E isomer.
Embodiment 27
E, E-3-methyl-5-[2-(1,1,3,3-tetramethyl--1,3-dihydro-5-isobenzofuran-base)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid
Adopt the step of example 2, make the product of use-case 26 make this title compound.
Embodiment 28
Z, E and E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid methyl esters
2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester ether solution together with excessive lithium aluminum hydride under reflux temperature of record in the example 1 was stirred 3 hours.Mixture water droplet after cooling off adds wherein.The ether layer then obtains 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-cyclohexenyl methyl alcohol with dried over sodium sulfate and evaporation.
Above-mentioned alcohol together stirred 5 hours together with the dichloromethane solution of excessive active hydrogen manganese oxide.Reaction mixture filtration, evaporation are then obtained 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene formaldehyde.
In the solution of the tetrahydrofuran (THF)/hexamethylphosphoramide that contains 1 equivalent sodium hydride (2: 1),, at room temperature stirred this reaction mixture 45 minutes at 0 ℃ of γ-dimethyl phosphine acyl group methacryloyl methyl esters that drips monovalent.Reactant is cooled to 0 ℃, and the above-mentioned monovalent aldehyde in the tetrahydrofuran (THF) that is adds wherein, at room temperature stirs this mixture 5 days.Water adds wherein, the mixture ether extraction.Ether extract is placed sodium sulfate top drying, filters, evaporates, then obtain title compound, it is an isomer mixture.
Embodiment 29
3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl) phenyl]-2, the 4-pentadienoic acid
By the mode identical with example 5, with 2-bromo-3,5,5,8,8-pentamethyl--5,6,7, the 8-naphthane reacts with 2-trifluoromethane sulfonyloxy ethyl benzoate, then make 2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl ethyl benzoate.
In the 10ml anhydrous diethyl ether that contains above-claimed cpd of 1.0g, add the 1.0M lithium aluminium hydride of 10ml, carry out aftertreatment, alcohol is emanated by the method for example 5.This alcohol is dissolved in the methylene dichloride, and the activated manganese dioxide of 6.0g adds wherein, and at room temperature stirred reaction mixture is three days.Then making 2-(3,5,5,8,8-pentamethyl--5,6,7,8-naphthane-2-yl)-phenyl aldehyde by diatomite filtration, evaporation, is a kind of yellow oil body.
In the 30ml tetrahydrofuran (THF) suspension that contains the 0.3g sodium hydride, add 1.42gr-dimethyl phosphine acyl group methyl methacrylate down in 0 ℃.20 ℃ were stirred this mixture 1 hour down.Above-mentioned aldehyde 1.1g is added wherein, at room temperature stirred the mixture 2 hours.The quick stoppage of reactant water, product is emanated with E and Z isomer mixture mode.Use the potassium hydroxide hydrolysis, then then obtain expecting product with the dilute hydrochloric acid souring soln, it is a kind of clear crystal.
mp=181-182℃.
1HNMR(CDCl 3):δ1.21(S,3H),1.26(S,3H),1.31(S,3H),
1.33(S,3H),1.70(S,4H),2.03(S,3H),2.11(S,3H),
5.83(S,1H),6.69(S,1H),6.71(S,1H),7.01(S,1H),7.34(d,
J=16.0Hz,1H),7.38(d,J=16.0Hz,1H),7.43-7.45(m,1H),
7.64-7.74(m,1H).
13CNMR (CDCl 3) downfield of ppm TMS: 13.77,19.18,
31.80,31.99,32.11,33.96,34.04,35.34,118.41,
125,65,127.30,128,17,128.43,130.50,132.06,132.84,
134.10,134.86,137.11,142.11,142.27,144.26,155.08,
171.96.
MS(CI):m/z?389(M ++H).
Embodiment 30
3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) phenyl]-2, the 4-pentadienoic acid
According to the step of example 29, with 2-bromo-5,5,8,8-tetramethyl--5,6,7, the 8-naphthane prepares title compound.
mp=178-179℃.
1HNMR(CDCl 3):δ1.27(s,6H),1.33(s,6H),1.72(s,4H),
2.25(s,3H),5.92(s,1H),6.78(d,J=16.0Hz,1H),7.14(d,
J=16.0Hz,1H),7.25(s,1H),7.33-7.38(m,1H),7.65-7.68(m,
1H).
13CNMR (CDCl 3) downfield of ppmTMS: 14.12,17.16,
31.87,31.93,34.31,35.13,118.35,126.29,126.50,
126.75,127.29；128.44,128.55,130.43,132.30,134.38,
134.92,137.24,142.26,144.05,144.28,155.22,170.51.
Embodiment 31
E, E-3-methyl-5-[2-(1,1,3,3-tetramethyl--1,3-dihydro-5-isobenzofuran-base)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid
According to the step of example 1 and example 2, use the product and the trifluoromethane sulfonyloxy cyclopentenes-1-yl carboxylic acid ethyl ester that are obtained from example 25 to prepare the title compound product, it is a kind of clear crystal.
mp=211-212℃.
1HNMR(CDCl 3):δ1.47(s,6H),1.54(s,6H),1.98-2.03(m,2H),
2.27(s,3H),2.71-2.76(m,2H),2.85-2.92(m,2H),
5.85(s,1H),6.30(d,J=16.0Hz,1H),7.02(s,1H),7.08(d,
J=16.0Hz,1H),7.11(d,J=16.0Hz,1H),7.23(d,
J=16.0Hz,1H).
MS(CI):m/z?353(M ++H).
Embodiment 32
E, E-3-methyl-5-[2-(1,1,3,3,6-pentamethyl--1,3-dihydro-5-isobenzofuran-base)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid
By example 31 methods, with 5-bromo-1,1,3,3,6-pentamethyl--1,3-dihydro-5-isobenzofuran reaction then makes expected compound, is a kind of clear crystal.
1HNMR(CDCl 3)δ1.49(s,6H),1.53(s,6H),2.02-2.07(m,2H),
2.16(s,3H),2.21(s,3H),2.67-2.78(m,4H),5.80(s,1H),
6.22(d,J=16.0Hz,1H),6.58(d,J=16.0Hz,1H),6.76(s,1H),
6.92(s,1H).
Embodiment 33
E, and E-3-methyl-5-[2-(2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentadiene-1-yl]-2,4-pentadiene alcohol
The product that is obtained from example 7 is used in the lithium aluminium hydride reduction in the ether, the quick stoppage of reaction mixture water, and the mixture that is generated ether extraction obtains the product of expecting after the evaporation.
In addition, be 94% to record following data during reduction as carrying out then productive rate in-78 ℃ with the DibalH in the methylene dichloride: 1H NMR 1(300MHz, CDCl 3): δ 1.25 (S, 6H), 1.30 (S, 6H), 1.68 (S, 4H), 1.99 (five peaks (pent), J=7.4Hz, 2H), 2.17 (S, 3H), 2.18 (S, 3H), 2.63-2.70 (m, 2H), 2.70-2.78 (m, 2H), 3.41 (d, J=6.4Hz, 1H), 6.99 (S, 1H), 7.10 (S, 1H) .IR (KBr, Cm -1: 3392brw, 3015qm, 2954m, 2863m, 1495m, 1455m, 1389m, 1362m, 1261m, 1085-963brs, 879m, 805m, 700m, MS (EI) m/z (relative intensity): 364 (M +, 40), 362 (M +-2.50), 347 (25), 337 (40), 321 (45), 297 (45), 281 (100), 229 (50).
High-resolution MS (EI) calculates C 26H 36O:364.2766; Actual measurement 364.2746.
Embodiment 34-41
With the product of expressing embodiment according to the mode of embodiment 33 be reduced into such as in the table 5 the corresponding alcohol that goes out of example.
Table 5
The embodiment numbering The embodiment product The product title
????34 ????2 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl-2-naphthyl)-1-tetrahydrobenzene-1-yl] 2,4-pentadiene alcohol
????35 ????6 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2,4-pentadiene alcohol
????36 ????4 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl-2-naphthyl)-1-cyclopentenes-1-yl]-2,4-pentadiene alcohol
????37 ????8 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-1-cyclopentenes-1-base-]-2,4-pentadiene alcohol
????38 ????29 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl) phenyl]-2,4-pentadiene alcohol
????39 ????30 E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) phenyl]-2,4-pentadiene alcohol
????40 ????31 E, and E-3-methyl-5-[2-(1,3-dihydro-1,1,3,3-tetramethyl--5-isobenzofuran-base)-1-cyclopentenes-1-yl]-2,4-pentadiene alcohol
????41 ????32 E, and E-3-methyl-5-[2-(1,3-dihydro-1,1,3,3,6-pentamethyl--5-isobenzofuran)-and 1-cyclopentenes-1-yl]-2,4-pentadiene alcohol
Embodiment 42
Z, E and E, E-3-methyl-5-[2-(4-methoxyl group-2)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid ethyl ester
Towards 1-bromo-4-methoxyl group-2,3, the pentane liquid through stirred solution tert-butyl lithium of adding 1.7M under-78 ℃ of the anhydrous tetrahydro furan of 6-trimethylbenzene then add zinc chloride (0.5M is dissolved in tetrahydrofuran (THF)).To room temperature, tetrakis triphenylphosphine palladium (O) and 2-trifluoromethane sulfonyloxy cyclic ethylene-1-yl carboxylic acid ethyl ester (in tetrahydrofuran (THF)) add in it with this mixture heating up, and the solution of generation stirred 2 hours under the reflux temperature of solvent.The cooling reactant adds the ether of 50ml to room temperature, separates the stratiform thing.Organic layer water aqueous carbonic acid hydrogen sodium and saturated sodium-chloride washing are done quick-fried with sodium sulfate.Separate (silica gel: hexane/ether 4: 1) then obtain 2-(4-methoxyl group-2)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester through evaporating solns, chromatography.
, then at room temperature stirred 15 minutes in 0 ℃ of anhydrous tetrahydrofuran solution that drips the 1.0N lithium aluminum hydride down to the solution of above-mentioned isolated solid in ether.Water droplet is added in the refrigerative reaction mixture, uses extracted with diethyl ether.Compile organic layer, use dried over sodium sulfate, evaporation, then make buttery alcohol.Oil is dissolved in the methyl alcohol, and to wherein adding the triphenylphosphine hydrobromide, reaction mixture at room temperature stirred 17 hours.Vacuum is removed solvent, and residue washs with ether, then makes corresponding phosphonium bromide, and it is dissolved in the dry dichloromethane, is cooled to 0 ℃ in argon atmospher, again to wherein adding sodium ethylate and 3-methyl-4-oxo butenoic acid ethyl.This mixture was stirred 1 hour the water quick stoppage down at 0 ℃.Dichloromethane extract is done quick-fried, evaporation with sodium sulfate, and (silica gel: purification hexane/ether 9: 1) then makes E, E and Z, the mixture of E ester to residue with chromatography.
Embodiment 43
E, E-3-methyl-5-[2-(4-methoxyl group-2)-1-tetrahydrobenzene-1-yl)-2, the 4-pentadienoic acid
To be obtained from the methanol solution chemical combination of the mixed ester product of example 42, under reflux temperature, stirred 3 hours with the aqueous potassium hydroxide of 2N.Reaction mixture is cooled to room temperature, be poured in the ice and the mixture of methylene dichloride, with the 3N hcl acidifying to pH be 3.With organic layer converge, dried over sodium sulfate and the evaporation, so then make a debris.Solid recrystallization from dehydrated alcohol then obtains expected compound.
Embodiment 44
E, E-3-methyl-5-[2-(1,13,3,6-pentamethyl--1,3-dihydro-5-isobenzofuran)-1-ring penta-1-yl]-2,4-or diolefinic acid
The step of Application Example 31, and with 5-bromo-1,1,3,3,6--methyl isobenzofuran replaces, and obtains title compound.
Embodiment 45
E, E-3-methyl-5-[2-(1,1,3,3,6-pentamethyl--1,3-dihydro-5-isobenzofuran-base)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid
Adopt the step of example 27 and replace 5-bromo-1,1,3,3,6-pentamethyl-isobenzofuran then makes title compound. 1H?NMR(CDCl 3)δ1.47(S,3H),1.50(S,3H),1.52(S,6H),1.70-1.86(m,4H),1.98(S,3H),2.16(S,3H),2.29-2.39(m,4H),5.75(S,1H),6.21(d,J=16.0Hz,1H),6.41(d,J=16.0Hz,1H),6.72(S,1H),6.91(S,1H)。
Embodiment 46
Z, E and E, E-3-trifluoromethyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid methyl esters
Under reflux temperature, stirred 3 hours at the solution of ether being described in 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl carboxylic acid ethyl ester in the example 1 and excessive lithium aluminum hydride.Cooling mixture, water droplet adds wherein.Organic layer is done quick-fried, evaporation with sodium sulfate, then obtains 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-cyclohexenyl methyl alcohol.
Above-mentioned alcohol was stirred 5 hours with the excessive Manganse Dioxide in methylene dichloride.Reaction mixture with sodium sulfate do quick-fried, filter, evaporation, then obtain 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene formaldehyde.
In the tetrahydrofuran (THF)/hexamethylphosphoramide (2: 1) that contains 1 normal lithium diisopropylamine, drip 1 normal β-trifluoromethyl-γ-diethyl phosphoryl methyl isobutyrate in 0 ℃.Reaction mixture at room temperature stirred 45 minutes, was cooled to 0 ℃ then, added 1 equivalent again and was dissolved in above-mentioned aldehyde in the tetrahydrofuran (THF) in wherein.Reaction mixture at room temperature stirred 24 hours.Water adds wherein, uses the ether extraction mixture.Organic layer is with dried over sodium sulfate, filtration, evaporation, then the title compound of isomer mixture form.
Embodiment 47
E, E-3-trifluoromethyl-5-[5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid
Will be by example 46 mixed ester product that makes and the 2N aqueous potassium hydroxide chemical combination that is dissolved in the methyl alcohol.Reaction mixture stirred 3 hours under reflux temperature, was cooled to room temperature, was poured in the mixture of ice and methylene dichloride again, was acidified to pH3.0 with 3N hydrochloric acid.With organic layer combination, dried over sodium sulfate and evaporation, then obtain resistates.Crude product is recrystallization from dehydrated alcohol, then obtains the expectation compound of lenticular.
Embodiment 48
2-trifluoromethane sulfonyloxy suberene carboxylic acid, ethyl ester
The 1 normal 2-suberone carboxylic acid, ethyl ester and the 1 normal diisopropylamine that will be dissolved in the methylene dichloride are cooled to 0 ℃, drip 1 normal Trifluoromethanesulfonic anhydride in wherein.Reaction mixture stirred under room temperature 5 hours, and by a series of filtered through silica gel, vacuum concentration, the resistates underpressure distillation then makes desired product.
Embodiment 49-55
With shown in Substrate react by example 48 modes, then make the corresponding triflate that table 6 is listed.
Embodiment 55-61
Shown Substrate is reacted by the mode that is equal to example 5 and example 6 basically, then obtain corresponding in the table 7 the product that goes out of example.
Table 6
Figure A0012808900681
Table 6 (continuing)
Table 7
Figure A0012808900701
Table 7 (continuing)
Embodiment 62
E, E-3-methyl-5-[2-(3-methoxyl group-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid
With adjacent bromobenzene methyl ether with 2,3-two chloro-2, (this reaction is recorded in the Eur.J.Med.Chem.-Chim.Ther by people such as P.Loeliger to the reaction of 3-dimethylbutane, 1980,15, in the 9-15-literary composition), then obtain 2-bromo-3-methoxyl group-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl-naphthalene reacts it then and then makes title compound with the method that is similar to example 2 and example 2.
Embodiment 63
E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--3-trifluoromethyl-2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid
To be dissolved in 1 equivalent 2-bromo-3,5,5,8 in the tetracol phenixin, 8-pentamethyl--5,6,7, the mixture of 8-naphthane and three normal N-bromosuccinimides are used 500W tungsten lamp irradiation 5 hours.With mixture cooling, filtration, solvent then obtains 2-bromo-5,6,7 through vacuum-evaporation, 8-tetrahydrochysene-5,5,8, and 8-tetramethyl--3-bromomethyl naphthalene is with its mixture hydrolysis with aqueous carbonic acid hydrogen sodium and acetone.This reactant is filtered, and vacuum is removed acetone.Residue is dissolved in the water, and carries out acidifying with dilute hydrochloric acid, then makes 3-bromo-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthoic acid.According to B.V.Kunshenko, J.Org.Chem.USSR (translator of English), the step in 10,8996 (1974) one literary compositions with this acid with SF4 and hydrogen fluoride reaction, then make 2-bromo-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--3-trifluoromethyl naphthalene reacts it and then to obtain title compound by example 1 and example 2 modes.
Embodiment 64
E, and E-3-methyl-5-[2-(2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentenes-1-yl]-2,4-pentadienoic acid methyl esters
At room temperature the compound of example 8 and the three silyl diazomethane reactions that are dissolved in benzene-methyl alcohol (7: 3) were then obtained the title compound of quantitative yield in 10 minutes.
m.p.=170-173℃.
1HNMR(300MHz,CDCl 3):δ1.25(s,6H),1.30(s,6H),
1.68(s,4H),2.02(pent,J=6.9Hz,2H),2.17(s,3H),
2.18(s,3H),2.63-2.71(m,2H),2.73-2.82(m,2H),
3.69(s,3H),5.78(s,1H),6.20(d,J=15.8Hz,1H),
6.65(d,J=15.8Hz,1H),6.96(s,1H),7.11(s,1H).
Embodiment 65
E, E-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-2-thienyl]-3-methyl-2,4-pentadienoic acid methyl esters
The 200ml benzole soln that will contain thiophene-3-formaldehyde, 40ml ethylene glycol and the 1.0g tosic acid of 50g refluxes and dewatered 6 hours.Evaporate this solvent and then obtain corresponding ethylene ketal.The 2.5M n-Butyl Lithium that is dissolved in hexane that this ketal solution of 15.61g and 50ml then will be arranged in the tetrahydrofuran (THF) of 120ml reacts in argon gas in-78 ℃, again with the triisopropyl boric acid of 31ml in 0 ℃ of reaction down.To the 2-bromo-5,6,7 that wherein adds 34.0 grams, 8-tetrahydrochysene-3,5,5,8,8-pentamethyl-naphthalene and 3.5 restrains tetrakis triphenylphosphine palladiums (O), and it is refluxed in argon gas then obtained corresponding 2-aryl-3-thiophene carboxylic aldehyde ethylene ketal in 8 hours.Its hydrolysis in acetone-water-tosic acid is then obtained corresponding aldehyde.Obtain title compound with the above-mentioned aldehyde of 1.3g and from the inner salt that the 3-methyl-4-solutions of dimethyl phosphoryl base M Cr makes of 1.6g and the hexamethylphosphoramide reaction of 0.3 sodium hydride that is dissolved in the 30ml tetrahydrofuran (THF) that restrains and 10ml.
m.p.=152-153℃.
1HNMR(CDCl 3):δ1.26(s,6H),1.32(s,6H),1.70(s,6H),
2.19(s,3H),2.22(s,3H),3.70(s,3H),5.82(s,1H),
6.62(d,J=16.0Hz,1H),6.68(d,J=16.0Hz,1H),7.15(s,1H),
7.19(s,1H),7.29(d,J=6.0Hz,1H),7.33(d,J=6.0Hz,1H)ppm.
Embodiment 66
E, E-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-3-thienyl]-3-methyl-2, the 4-pentadienoic acid
With the title compound of 3N potassium hydroxide hydrolysis example 65, then carry out acidifying and then obtain above-mentioned title compound with the hydrochloric acid of 3N.m.p.=194-195℃
1HNMR(CDCl 3):δ1.26(s,6H),1.32(s,6H),1.70(s,6H),
2.20(s,3H),2.23(s,3H),5.84(s,1H),6.63(d,J=16.0Hz,1H),
6.73(d,J=16.0Hz,1H),7.15(s,1H),7.20(s,1H),
7.29(d,J=6.0Hz,1H),7.34(d,J=6.0Hz,1H)ppm.
Embodiment 67
E, E-5-[3-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-2-thienyl]-3-methyl-2, the 4-pentadienoic acid
To the 2-bromo-5,6,7 that contains 17.0g, 8-tetrahydrochysene-3,5,5,8 adds the pentane liquid of 1 normal tert-butyl lithium in the 60ml tetrahydrofuran compound of 9-pentamethyl-naphthalene, stirred 30 minutes, then at room temperature stirs 1 hour in-78 ℃ of argon gas.This mixture is cooled to-78 ℃ then,, earlier it was stirred 1 hour, then restir 2 hours at room temperature to the triisopropyl boric acid ester that wherein adds 20ml.With the corresponding boric acid that obtains after the salt acid treatment with the pesquihydrate form.To be dissolved in 3.0g3-bromo thiophene carboxylate methyl ester solution in 14ml dimethoxy ethane and the tetrakis triphenylphosphine palladium (O), then be the ethanol liquid that contains above-mentioned boric acid, be that the saturated sodium bicarbonate solution of 50ml refluxed in argon gas 3 hours then.Water obtains 3-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl) thiophene-2-carboxylic acid methyl esters, m.p.89-90 ℃ after handling.
Reduce this ester with excessive lithium aluminium hydride, then the alcohol that is generated with the Manganse Dioxide oxidation then obtains corresponding aldehyde.This aldehyde according to the same interior reactant salt that results from 3-methyl-4-solutions of dimethyl phosphoryl base M Cr of the mode that is similar to example 65, is obtained the title compound with the methyl ester form.With 2N KOH hydrolysis, then, then obtain title compound, m.p.=208-209 ℃ with 3N HCl acidifying.
1HNMR(CDCl 3):δ1.26(s,6H),1.32(s,6H),1.70(s,4H),
2.17(s,3H),2.22(s,3H),5.85(s,1H),6.65(d,J=16.0Hz,1H),
6.93(d,J=16.0Hz,1H),7.01(d,J=5.0Hz,1H),7.07(s,1H),
7.20(s,1H),7.25(d,J=5.0Hz,1H)ppm.
Embodiment 68
(Z, E-5-[3-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2-propenylidene-2, the 4-thiazolidinedione
(1.53g 8.38mmol) is dissolved in and adds 89mg (0.34mmol) 18-hat (ether)-6 in the phosphoryl 3-acetic acid methyl ester in the 30ml tetrahydrofuran (THF) to 1.36ml.This solution is cooled to 0 ℃, is added dropwise to 0.5M hexamethyldisilazane/toluene solution of 6.70ml (3.35mmol) again.Through 0 ℃ down stir 30 minutes after, be dissolved in 2-(3,5,5,8,8-pentamethyl--5,6,7, the 8-naphthane-2-yl) tetrahydrobenzene-1-carboxylic aldehyde of 10ml tetrahydrofuran (THF) by sleeve pipe Dropwise 5 20mg, 23 ℃ are stirred this down and generate mixture 65 hours.With the saturated NH of 10ml 4After the quick stoppage of the Cl aqueous solution, this reaction mixture impouring to 50ml salt solution, is extracted with 3 * 50ml ether.The organic layer that converges is with the water washing of 2 * 50ml salt, MgSO 4Do quick-fried, filter and evaporation, then obtain a kind of colourless oil body.Flash chromatography separates on silica gel, with hexane/CH 2Cl 2(2/1 to 1/1) wash-out then obtains the E-3-[2-[(3 of 578mg (1.58mmol, 94% productive rate), and 5,5,8,8-pentamethyl--5,6,7,8-naphthane-2-yl)]-the 1-cyclohexenyl] methyl acrylate is a kind of colourless oil body.
1H?NMR(300?MHz,CDCl 3):d1.24(s,6H),1.28(s,3H),
1.30(s,3H),1.67(s,4H),1.70-1.84(m,4H),2.07
(s,3H),2.10-2.37(m,4H),3.65(s,3H),5.80(d,J
=15.8Hz,1H),6.86(s,1H),7.07(s,1H),7.18(d,
J=15.8Hz,1H)； 13C?NMR(75MHz,CDCl 3):d19.1,
22.5,22.7,25.0,31.9,32.0,32.1,33.6,33.9,34.0,
35.4,51.1,11?4.7,126.5,127.9,129.7,131.7,138.6,
142.1,143.7,145.1,148.7,168.1；IR(Nujol,cm -1):
3015m,2926s,2859s,1723s,1617m,1496m,1455m,1434s,
1307s,1295s,1273s,1189m,1133s,1071m,987m,856m；MS
(EI) m/z (relative intensity): 366 (M +, 100), 351 (M +-CH 3
,75),319(60),295(25),281(45),241(45),165
(25), 111 (100); HRMS (EI) calculates C 25H 34O 2: 366.2559;
Actual measurement 366.2549; Analytical calculation-C 25H 34O 2: C, 81.92, H,
9.35. actual measurement: C, 82.19, H, 9.39, in addition to 18mg
The isomer of the light yellow oily of (O.05mmol, a2% productive rate)
1H?NMR(300MHz,CDCl 3):d1.20(s,3H),
1.24(s,3H),1.26(s,6H),1.65(s,4H),1.68-1.80
(m,4H),2.09(s,3H),2.08-2.34(m,4H),3.72(s,3
H),5.44(d,J=12.7Hz,1H),6.23(d,J=12.7Hz,1
H),6.87(s,1H),7.03(s,1H)；IR(Nujol,cm -1):
3017m,2957s,2859s,1724s,1618m,1496m,1457m,1437m,
1363w,1227-1171brs,758s；MS(EI)m/z(relative
intensity):366(M +,100),351(M +-CH 3,75),319(60),
281(5O),241(40),111(100).
Under-78 ℃, be dissolved in 25ml CH to 470mg (1.28mmol) 2Cl 2In above-mentioned ester in add the 1.0M Dibal/ hexane solution of 2.82ml (2.82mmol).After 30 minutes under-78 ℃ to the 1.0M Dibal/ hexane solution that wherein adds 1.0ml (1.00mmol).The reaction mixture saturated soluble tartrate sodium water solution quick stoppage of 10ml, restir is heated to 23 ℃ and is thirty minutes long.The mixture that is generated is poured among the 1N NaOH of 50ml, and with the ether extraction of 3 * 50ml, the organic layer that will converge is with the H of 1 * 100ml 2O, the water washing of 1 * 100ml salt, use Na 2SO 4Drying, filtration and evaporation then obtain a kind of colourless oil body.Flash chromatography separates on silica gel, with hexane/EtOAc (8/1 to 4/1) wash-out, then obtains the E-3-[2-[(3 of 430mg (1.27mmol, 99% productive rate), 5,5,8,8-pentamethyl--5,6,7,8-naphthane-2-yl)]-the 1-cyclohexenyl]-2-propylene-1-alcohol, be a kind of buttery white solid.Rf=0.21 (8/1 hexane/EtOAc):
1H?NMR(300?MHz,CDCl 3):d1.23(s,3H),1.24(s,3H),
1.28(s,3H),1.29(s,3H),1.67(s,4H),1.65-1.82
(brm,4H),2.07(s,3H),2.10-2.37(m,5H),4.04(t,
J=6.3Hz,2H),5.74(dt,J=15.8,9.1Hz,1H),6.03
(d,J=15.8Hz,1H),6.89(s,1H),7.05(s,3H)；13C
NMR(75MH2z,CDCl 3):d19.0,22.9,23.1,25.2,31.9,
32.0,32.1,33.0,33.9,35.4,64.3,124.9,126.5,127.6,
129.5,132.0,132.5,139.7,140.1,142.0,143.0；IR
(KBr,cm -1):3467brm,3033w,3014w,2961s,2927s,2855s,
2835m,1641w,1495m,1457brm,1389w,1361w,1234w,
1110w, 1035w, 1010m, 973m, 894w; MS (EI) m/z relative intensity
:339(M +,50),323(M +-CH 3,20),305(30),
293 (50), 237 (35), 223 (25), 111 (100); Analytical calculation
: C, 85.15, H, 10.12. surveys C, 84.27, H, 10.29.
Be dissolved in 25ml CH towards 570mg (1.34mmol) under 23 ℃ 2Cl 2In Dess-Martin Periodirarle in splash into 364mg (1.08mmol) by sleeve pipe and be dissolved in 10ml CH 2Cl 2Above-mentioned alcoholic solution in.23 ℃ were stirred down after 1.5 hours, this reaction mixture is poured into contains 5 gram Na 2S 2O 3The saturated NaHCO of 50ml 3In the aqueous solution, stir tempestuously, clear until each layer.Organic layer is separated, and the remaining aqueous mixture is with 2 * 25mlCH 2Cl 2Extract,, use MgSO the organic phase combination 4Drying, filtration, evaporation then obtain a kind of colourless oil body.Flash chromatography separates on silica gel, with hexane/ethyl acetate (8/1) wash-out, then obtains the E-3-[2-[(3 of 276mg (0.82mmol, 76% productive rate), 5,5,8,8-pentamethyl--5,6,7,8-naphthane-2-yl)]-the 1-cyclohexenyl] propenal is a kind of colourless oil body.Rf=0.48 (8/1 hexane/EtOAC); 1NMR (300MHZ,
CDCl 3):d1.23,(s,3H),1.26(s,3H),1.29(s,3H),
1.31(s,3H),1.68(s,4H).1.71-1.83(brm,4H),2.09
(s,3H),2.22-2.40(m,4H),6.09(dd,J=8.0,15.7
Hz,1H),6.88(s,1H),6.95(d,J=15.7Hz,1H),
7.10(s,1H),9.31(d,J=8.0Hz,1H)； 13C?NMR(75
MHz,CDCl 3):d19.0,22.4,22.6,25.0,31.8,31.9,32.0,
33.8,34.0,35.2,126.3,126.4,128.1,130.4,131.6,
138.3,142.4,144.5,151.4,152.8,190.3；R(Nujol,cm
-1):3016w,2958s,2928s,2863m,1680s,1609m,1496w,
1457m, 1363w, 1274-973brm, 756w; MS (EI) m/z (relative intensity
):336(M +,100),321(M +-CH 3,75),307(45),
295 (50), 229 (75), 111 (70); HRMs (EI) calculates
C 24H 32O:336.2453; Actual measurement 336.2457.
In the above-mentioned aldehyde of 238mg (0.71mmol), add 20ml toluene, 99mg (0.85mmol) 2,4-thiazolidinedione, 40ml (30mg, piperidines 0.35mmol), 20ml (21mg, the active powder 4A molecular sieve of Glacial acetic acid 0.35mmol) and 1g.Heating is after 2 hours down through 80 ℃, and the yellow soup compound that is generated is by 1, and " the diatomite backing plate filters, and the filtrate that obtains is used the saturated NaHCO of 1 * 50ml again with the dilution of 100ml ether 3The saline water extraction of the aqueous solution, 1 * 50ml is used MgSO 4Dry, obtain a kind of yellow oil body after filtration with after the evaporation.Flash chromatography separates on silica gel, then obtains the title compound of 138mg (0.32mmol, 45% productive rate) with petrol ether/ethyl acetate (8/1 to 4/) wash-out, is a kind of yellow solid.Rf=0.42 (2/1 hexane/EtOAc); 1HNMR
(300MHz,CDCl 3):d1.24(s,6H),1.29(s,3H),1.33
(s,3H),1.69(s,4H),1.76-1.85(brm,4H),2.05(s,
3H),2.31-2.40(brm,4H),6.00(dd,J=11.5,15.0Hz,
1H),6.04(d,J=15.0Hz,1H),6.85(s,1H),7.09
(s,1H),7.26(s,1H),8.10(brs,1H)； 13C?NMR(75
MHz,CDCl 3):d19.0,22.5,22.6,24.9,32.0,32.1,33.8,
34.0,34.1,35.3,119.8,121.0,126.1,127.8,131.0,
131.7,135.6,138.6,142.4,144.0,145.7,149.1,165.6,
166.5；IR(KBr,cm -1):3330brw,3262brw,3015w,2958m,
2927m,2860w,1741m,1688s,1588m,1496w,1456w,1390w,
1362m, 1331m, 1169w, 1145w, 970vw; MS (EI) m/z (relative intensity
1:435(M +,100),420(M +-CH 3,20),366(45),
278 (25), 111 (5); HRMS (EI) calculates C 27H 33NO 2S:
435.2232; Actual measurement 435.2232.

Claims (33)

1. formula I compound:
Figure A0012808900021
A wherein, B and C are CH, CH 2, O or S, and have 1 heteroatoms; D is (CH) m, M is the integer of 0-1; Perhaps D is (CH 2) n, n is the integer of 0-2; Dotted line ... expression exists or non-existent pair of key, if thereby only have two keys then be positioned at the a-b position, if having a plurality of pairs of keys then they are in conjugate position to form aromatic ring; R is a hydrogen, methyl, ethyl, the tertiary butyl or trifluoromethyl; Ar is as the lower section chemical formula:
Figure A0012808900022
R wherein 1, R 2, R 3And R 4Be hydrogen, (C 1-3) alkyl, (C 1-3) alkoxyl group or trifluoromethyl; As the lower section chemical formula:
Figure A0012808900031
R wherein 5Be hydrogen, (C 1-3) alkyl, methoxyl group or trifluoromethyl; And R 6Be hydrogen, methyl or ethyl; As the lower section chemical formula
Figure A0012808900032
R wherein 6Be hydrogen, methyl or ethyl; R 7Be hydrogen, methyl or ethyl; Y is that hydrogen and X are CH 2OH, CHO, COOH, CN, CH 2CONH 2Or as the lower section chemical formula:
Figure A0012808900033
R wherein 8Be straight or branched (C 1-8) alkyl, or
Figure A0012808900041
Here R 9Be hydrogen, straight or branched (C 1-10) alkyl, glycosyl, the 2-methoxyethyl, 2-diformazan aminoethyl, (1,2, or 3)-pyridyl, or (1,2, or 3)-picolyl; Perhaps X and Y connect together and form the thiazolidinedione ring of following formula: And their pharmacologically acceptable salts and ester.
2. formula I compound; The formula I is A wherein, and B and C are CH, CH 2, O or S, and have 1 heteroatoms; D is (CH) m, m is the integer of 0-1; Perhaps D is (CH 2) n, n is the integer of 0-2, dotted line ... expression exists or non-existent pair of key, if thereby only have two keys then be positioned at the a-b position, if having a plurality of pairs of keys then they are in conjugate position to form aromatic ring; R is a hydrogen, methyl, ethyl, the tertiary butyl or trifluoromethyl; Ar is as the lower section chemical formula:
Figure A0012808900051
R wherein 1, R 2, R 3And R 4Be hydrogen, (C 1-3) alkyl, (C 1-3) alkoxyl group or trifluoromethyl; And X is CH 2OH, CHO, COOH, CN, CH 2CONH 2Or as the lower section chemical formula:
Figure A0012808900052
R wherein 8Be straight or branched (C 1-8) alkyl, or
Figure A0012808900053
Here R 9Be hydrogen, straight or branched (C 1-10) alkyl, glycosyl, the 2-methoxyethyl, 2-diformazan aminoethyl, (1,2, or 3)-pyridyl, or (1,2, or 3)-picolyl; Y is a hydrogen; And their pharmacologically acceptable salts and ester.
3. formula I compound:
Figure A0012808900061
Formula I wherein A is CH or CH 2, B and C are CH, CH 2, O or S, and have 1 heteroatoms; D is (CH) m, m is the integer of 0-1; Perhaps D is (CH 2) n, n is the integer of 0-2; Dotted line ... expression exists or non-existent pair of key, if thereby only have two keys then be positioned at the a-b position, if having a plurality of pairs of keys then they are in conjugate position to form aromatic ring; R is a hydrogen, methyl, ethyl, the tertiary butyl or trifluoromethyl; Ar is as the lower section chemical formula: R wherein 5Be hydrogen, (C 1-3) alkyl, alkoxyl group or trifluoromethyl; R 6Be hydrogen, methyl or ethyl; X is CH 2OH, CHO, COOH, CN, CH 2CONH 2Or as the lower section chemical formula:
Figure A0012808900071
R wherein 8Be straight or branched (C 1-8) alkyl, or Here R 9Be hydrogen, straight or branched (C 1-10) alkyl, glycosyl, the 2-methoxyethyl, 2-diformazan aminoethyl, (1,2, or 3)-pyridyl, or (1,2, or 3)-picolyl; Y is a hydrogen, and their pharmacologically acceptable salts and ester.
4. formula I compound;
Figure A0012808900073
Wherein A is CH, CH 2, B is that C is CH, CH 2, O or S, and have 1 heteroatoms; D is (CH) m, m is the integer of 0-1; Perhaps D is (CH 2) n, n is the integer of 0-2; Dotted line ... expression exists or non-existent pair of key, if thereby only have two keys then be positioned at the a-b position, if having a plurality of pairs of keys then they are in conjugate position to form aromatic ring; R is a hydrogen, methyl, ethyl, the tertiary butyl or trifluoromethyl; Ar is as the lower section chemical formula: R wherein 6Be hydrogen, methyl or ethyl; R 7Be hydrogen, methyl or ethyl; X is CH 2OH, CHO, COOH, CN, CH 2CONH 2Or as the lower section chemical formula:
Figure A0012808900082
R wherein 8Be straight or branched (C 1-8) alkyl, or
Figure A0012808900083
Here R 9Be hydrogen, straight or branched (C 1-10) alkyl, glycosyl, the 2-methoxyethyl, 2-diformazan aminoethyl, (1,2, or 3)-pyridyl, or (1,2, or 3)-picolyl; Y is a hydrogen, and their pharmacologically acceptable salts and ester.
5. according to the compound of claim 3, Z, E and E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid ethyl ester.
6. according to the compound of claim 3, E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid.
7. according to the compound of claim 3, Z, E and E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-cyclopentenes-1-yl]-2,4-pentadienoic acid ethyl ester.
8. according to the compound of claim 3, E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid.
9. according to the compound of claim 3, Z, E and E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-tetrahydrobenzene-1-yl]-2,4-pentadienoic acid ethyl ester.
10. according to the compound of claim 3, E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid.
11. according to the compound of claim 3, Z, E and E, E-3-methyl-5-[2-(2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentenes-1-yl]-2,4-pentadienoic acid ethyl ester.
12. according to the compound of claim 3, E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid.
13. according to the compound of claim 3,3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl) phenyl]-2, the 4-pentadienoic acid.
14. according to the compound of claim 3, (Z, E)-5-[3-[2-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2-propenylidene-2, the 4-thiazolidinedione.
15. according to the compound of claim 3,3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-phenyl]-2, the 4-pentadienoic acid.
16. according to the compound of claim 4, E, E-3-methyl-5-[2-(1,1,3,3-tetramethyl--1,3-dihydro-5-isobenzofuran-base)-1-ring penta-1-yl]-2, the 4-pentadienoic acid.
17. the method disposing and prevent the Mammals coronary artery disease comprises claim 1 compound medicine to the effective therapeutic dose of Mammals.
18. a method that increases mammalian plasma HDL content comprises claim 1 compound medicine to the effective therapeutic dose of described Mammals.
19. the method disposing and prevent human atheromatosis comprises claim 1 compound medicine to effective therapeutic dose.
20. according to the method for claim 17, wherein said compound is E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentenyl]-2, the 4-pentadienoic acid.
21. according to the method for claim 17, wherein said compound is E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid.
22. according to the method for claim 18, wherein said compound is E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentenyl]-2, the 4-pentadienoic acid.
23. according to the method for claim 18, wherein said compound is E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid.
24. according to the method for claim 19, wherein said compound is E, E-3-methyl-5-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-tetrahydrochysene-2-naphthyl)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid.
25. according to the method for claim 19, wherein said compound is E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-tetrahydrobenzene-1-yl]-2, the 4-pentadienoic acid.
26. a method for the treatment of the cancer of bringing out of mammalian tumor cell differentiation comprises claim 1 compound medicine to the effective therapeutic dose of described Mammals.
27. according to the compound of claim 26, it is E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-hexamethylene-1-yl]-2, the 4-pentadienoic acid.
28. according to the compound of claim 26, be E, E-3-methyl-5-[2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-cyclopentenes-1-yl]-2, the 4-pentadienoic acid.
29. a method for preparing the chemical formula I compound of claim 1,
Figure A0012808900111
The formula I is Ar wherein, A, B, C, D, a, b, R and dotted line ... qualification described with claim 1; This method comprises the compound with formula ArBr or ArI, and with the lithium alkylide reaction, condition is that the temperature in-78 ℃ to 30 ℃ is carried out in inert solvent, adds ZnCl subsequently 2, obtain the compound of formula ArZnCl, this compound itself and the reaction of formula II compound,
Figure A0012808900121
The formula II wherein exists palladium to urge ° to change an agent, in inert solvent in 10-60 ℃ of reaction; Get formula III compound:
Figure A0012808900122
Formula III formula III compound solvent in inertia reacts with a kind of hydride reducer in 0-60 ℃, obtains formula IV compound: The formula IV obtains formula V compound with formula IV compound and three substituting group phosphine reaction of hydrogen bromide:
Figure A0012808900131
The formula V with formula V compound inert solvent in 0 ℃ down with a kind of alkali reaction, add subsequently a kind of as shown in the formula aldehyde:
Figure A0012808900132
Wherein R limits with claim 1, and X is COOR 8And R 8Qualification obtains formula I compound with claim 1.
30. a method for preparing the compound of claim 1, Ar wherein, A, B, C, D, a, b, R and dotted line (...) such as claim 1 qualification, X is CHO; This method comprises formula I compound:
Figure A0012808900141
The formula I is Ar wherein, A, and B, C, D, a, b, R and dotted line (...) such as claim 1 qualification, X is COOH or COOR 8, and R 8Limit with claim 1; With hydride reducer in inert solvent in 0-60 ℃ of reaction, obtaining X is CH 2The formula I compound of OH is CH with X 2The formula I compound of OH obtains the formula I compound that X is CHO with oxidizer treatment.
31. a method for preparing claim 1 formula I compound,
Figure A0012808900142
Ar wherein, A, B, C, D, a, b and R are with the qualification of claim 1, and X is C (O)-NHR 9, and R 9Limit with claim 1, this method comprises the compound as shown in the formula I: The formula I is Ar wherein, A, and B, C, D, a, b and R are with the qualification of claim 1, and X is COOR 8, and R 8Limit with claim 1, with a kind of alkali under hydrolysising condition in 30-100 ℃ of reaction, obtain the formula I compound that X is COOH with the mineral acid acidifying then, with this X be again the formula I compound of COOH in inert solvent in 0-25 ℃ with activator react intermediate product, add R to this intermediate product 9NH 2A kind of amine, R 9Limit as claim 1, obtain formula I compound.
32. a method for preparing claim 1 formula I compound, The formula I is Ar wherein, A, and B, C, D, a, b and R are with the qualification of claim 1, and X is-CO 2R 8And R 8Limit with claim 1, this method comprises the compound as shown in the formula IV: Wherein Ar and Y qualification together is the same, obtains formula VIII compound in 0-40 ℃ with a kind of oxidant reaction in inert solvent:
Figure A0012808900162
This formula VIII compound with as shown in the formula a kind of in reactant salt:
Figure A0012808900163
Condition is to have a kind of alkali in inert solvent, obtains formula I compound.
33. a pharmaceutical compositions comprises claim 1 compound and suitable carriers.
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CZ288526B6 (en) * 1994-08-10 2001-07-11 F. Hoffmann-La Roche Ag Derivatives of tetrahydronaphthalene or indane, pharmaceutical preparations based thereon and intermediates for preparing these derivatives

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EP0718285A3 (en) 1996-08-07
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EP0718285A2 (en) 1996-06-26
IL116259A (en) 2000-07-16
BR9505938A (en) 1997-12-23
AU690772B2 (en) 1998-04-30
CA2165374A1 (en) 1996-06-20
EP0718285B1 (en) 2001-04-11
IL116259A0 (en) 1996-03-31
FI956086A0 (en) 1995-12-18
HU9503627D0 (en) 1996-02-28
AU4043895A (en) 1996-06-27
ATE200481T1 (en) 2001-04-15
CN1176248A (en) 1998-03-18
JPH08291094A (en) 1996-11-05
FI956086A (en) 1996-06-20
HUT74007A (en) 1996-10-28

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